Cyclic natriuretic peptide constructs

A peptide construct of formula III:

• wherein:
• Aaa1 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• Nle, Ala, Leu, Ile, Val, Arg, Phe, Lys, Tyr, Asp, Nva, Met, Met(O), or Met(O2), or an α, α-disubstituted amino acid derived from Nle, Ala, Leu, Ile, Val, Arg, Phe, Lys, Tyr, Asp, Nva, Met, Met(O), or Met(O2), including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa1 is an acyl comprising a C2 to C18 linear alkyl, a C3 to C17 branched alkyl, a C2 to C18 linear alkenyl or alkynyl or a C3 to C18 branched alkenyl or alkynyl, or Aaa1 is an amino acid surrogate of the structure:
• wherein the broken line indicates a peptide bond;
• R and R′are independently H, a linear or branched C1 to C6 aliphatic chain, —(CH2)y—S—CH3, —(CH2)y—S(═O)—CH3, —(CH2)y—S(O2)—CH3, a bond and a cyclopropane, cyclobutane, cyclopentane, or cyclohexane ring, or a C1 to C3 aliphatic chain and a cyclopropane, cyclobutane, cyclopentane, or cyclohexane ring;
• x is 1 or 2;
• Y is CH2 or C═O;
• W is CH2, NH or NR′″;
• Z is H or CH3;
• Q is —H, —(CH2)m—N(v3)(v4), —(CH2)m—CH3, —(CH2)m—O(v3), —(CH2)m—C(═O)-(v3), —(CH2)m—C(═O)—O-(v3), —(CH2)m—S(v3), —C(═O)—(CH2)m—CH3, —C(═O)—(CH2)m—N(v3)(v4), —C(═O)—(CH2)m—C(═O)-(v3), —C(═O)—(CH2)m—O(v3), or —C(═O)—(CH2)m—S(v3);
• R′″ is an acyl, a C1 to C17 linear or branched alkyl chain, a C2 to C19 linear or branched alkyl acyl chain, a C1 to C17 linear or branched omega amino aliphatic, or a C1 to C17 linear or branched omega amino aliphatic acyl;
• n is 0, 1 or 2;
• m is 0 to 17;
• y is 1 to 5;
• v3 and v4 are each independently H, a C1 to C17 linear or branched alkyl chain or a C2 to C19 linear or branched alkyl acyl chain, on the proviso that if one of v3 or v4 is an alkyl acyl chain, then the other of v3 or v4 is H;
• and the carbon atoms marked with an asterisk can have any stereochemical configuration;
• Aaa2 and Aaa13 are the same or different, and are each L- or D-isomer amino acid residues forming a cyclic bridge through the side chains of each of Aaa2 and Aaa13, wherein the linking group of the cyclic bridge is R1 selected from the group consisting of:
• —S—S—, —S—CH2—S—, —S—CH2—, —CH2—S—, —C(═O)—NH—, —NH—C(═O)—, —CH2—NH—, —NH—CH2—, —CH2—S(O)n— where n is 1 or 2, —S(O)n—CH2— where n is 1 or 2, —CH2—CH2—, —CH═CH— (E or Z), —C≡C—, —C(═O)—O—, —O—C(═O)—, —C(═O)—CH2—, —CH2—C(═O)—, —O—C(═O)—NH—, —NH—C(═O)—O—, or —NH—C(═O)—NH—;
• Aaa3 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• His, Ala, Ser, Thr, Lys, HLys, Orn, Cys, HCys, Dap, or Dab, or an α, α-disubstituted amino acid derived from His, Ala, Ser, Thr, Lys, HLys, Orn, Cys, HCys, Dap, or Dab, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa3 is an amino acid surrogate of the structure:
• where R and R′ are independently H or an amino acid side chain moiety of His, Ala, Ser, Thr, Lys, HLys, Orn, Cys, HCys, Dap, or Dab or a derivative of an amino acid side chain moiety of His, Ala, Ser, Thr, Lys, HLys, Orn, Cys, HCys, Dap, or Dab;
• x is 1 or 2;
• Y is CH2 or C═O;
• W is CH2, NH or NR′″;
• Z is H or CH3;
• R′″ is an acyl, a C1 to C17 linear or branched alkyl chain, a C2 to C19 linear or branched alkyl acyl chain, a C1 to C17 linear or branched omega amino aliphatic, or a C1 to C17 linear or branched omega amino aliphatic acyl;
• and n is 0, 1 or 2;
• Aaa4 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Nle, Nva or Tle, or an α, α-disubstituted amino acid derived from substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Nle, Nva or Tle, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa4 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Nle, Nva or Tle or a derivative of an amino acid side chain moiety of substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Nle, Nva or Tle;
• Aaa5 is Gly, Sar, Aib, an L- or D-isomer of Ala, or Aaa5 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or —CH3;
• Aaa6 is Gly, Sar, Aib, an L- or D-isomer of Ala, or Aaa6 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or —CH3;
• Aaa7 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• Arg, His, Ala, Ser, HSer, Thr, Lys, HLys, Orn, Cys, HCys, Cit, Abu, Dap, or Dab, or an α, α-disubstituted amino acid derived from Arg, His, Ala, Ser, HSer, Thr, Lys, HLys, Orn, Cys, HCys, Cit, Abu, Dap, or Dab, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa7 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Arg, His, Ala, Ser, HSer, Thr, Lys, HLys, Orn, Cys, HCys, Abu, Dap, or Dab or a derivative of an amino acid side chain moiety of Arg, His, Ala, Ser, HSer, Thr, Lys, HLys, Orn, Cys, HCys, Abu, Dap, or Dab;
• Aaa8 is Gly, an L- or D-isomer of an α-amino acid selected from the group consisting of:
• from Nle, Ile, Leu, Val, Phe, Ala, Nva, Met(O), Met(O2), or Tle, or an α, α-disubstituted amino acid derived from Nle, Ile, Leu, Val, Phe, Ala, Nva, Met(O), Met(O2), or Tle, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa8 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Nle, Ile, Leu, Val, Phe, Ala, Nva, Met(O), Met(O2), or Tle, or a derivative of an amino acid side chain moiety of Nle, Ile, Leu, Val, Phe, Ala, Nva, Met(O), Met(O2), or Tle;
• Aaa9 is an L- or D-isomer of an α-amino acid selected form the group consisting of:
• Asp, Glu, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Met(O2), Orn, Dap, or Dab, or an α, α-disubstituted amino acid derived from Asp, Glu, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Met(O2), Orn, Dap, or Dab, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa9 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Asp, Glu, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Met(O2), Orn, Dap, or Dab or a derivative of an amino acid side chain moiety of Asp, Glu, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Met(O2), Orn, Dap, or Dab;
• Aaa10 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• Arg, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Cit, Met(O), Orn, Dap, or Dab, or an α, α-disubstituted amino acid derived from Arg, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Orn, Dap, or Dab, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa10 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Arg, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Cit, Met(O), Orn, Dap, or Dab or a derivative of an amino acid side chain moiety of Arg, His, Ala, Ser, Thr, Lys, HLys, Cys, HCys, Met(O), Orn, Dap, or Dab;
• Aaa11 is Gly or a D- or L-isomer of an α-amino acid selected from the group consisting:
• from Nle, Ile, Leu, Val, Phe, Ala, Nva, Cys, HCys, Abu or Tle, or an α, α-disubstituted amino acid derived from Nle, Ile, Leu, Val, Phe, Ala, Nva, Cys, HCys, Abu or Tle, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa11 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Nle, Ile, Leu, Val, Phe, Ala, Nva, Cys, HCys, Abu or Tle or a derivative of an amino acid side chain moiety of Nle, Ile, Leu, Val, Phe, Ala, Nva, Cys, HCys, Abu or Tle;
• Aaa12 is Gly, an L- or D-isomer of an α-amino acid selected from the group consisting of:
• from Ser, Nle, Ile, Leu, Val, Phe, Ala, Nva, Arg, Lys, Orn, Cys, HCys, Abu or Tle, or an α, α-disubstituted amino acid derived from Ser, Nle, Ile, Leu, Val, Phe, Ala, Nva, Arg, Lys, Orn, Cys, HCys, Abu or Tle, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa12 is an amino acid surrogate as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of Ser, Nle, Ile, Leu, Val, Phe, Ala, Nva, Arg, Lys, Orn, Cys, HCys, Abu or Tle or a derivative of an amino acid side chain moiety of Ser, Nle, Ile, Leu, Val, Phe, Ala, Nva, Arg, Lys, Orn, Cys, HCys, Abu or Tle;
• Aaa14 is an L- or D-isomer of an α-amino acid selected from the group consisting of:
• substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Lys, Orn, Nle, Nva or Tle, or an α, α-disubstituted amino acid derived from substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Lys, Orn, Nle, Nva or Tle, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa14 is an amino acid surrogate of the structure of formula II as for Aaa3 where R and R′ are independently H or an amino acid side chain moiety of substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Lys, Orn, Nle, Nva or Tle or a derivative of an amino acid side chain moiety of substituted or unsubstitued Phe, HPhe or Pgl, or Tyr, Leu, Ile, Val, Ala, Lys, Orn, Nle, Nva or Tle;
• Aaa15 is a D- or L-isomer of an α-amino acid selected from the group consisting of:
• Ala, Arg, Orn, Lys, Dap, Dab, HArg, or HLys, or an α, α-disubstituted amino acid derived from Ala, Arg, Orn, Lys, Dap, Dab, HArg, or HLys, including all (R) or (S) configurations of α, α-disubstituted amino acids where the substituents are different, or Aaa15 is an amino acid surrogate of the structure:
• wherein the broken line indicates a peptide bond;
• at least one of R and R′ is (CH2)y—R″ and if one, the remaining of R and R′ is H, where R″ is:
• —NH2, —NH—C(═NH)—NH2, —NH—(CH2)y—NH2, —NH—C(═O)—NH2, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—NH—(CH2)y—NH2, —NH—C(═NH)—NH-Me, —NH—C(═NH)—NH-Et, —NH—C(═NH)—NH—Pr, —NH—C(═NH)—NH—Pr-i, —NH—C(═O)—CH3, —NH—C(═O)—CH2—CH3, —NH—C(═O)—CH—(CH3)2, —NH—C(═O)—O—CH3, —NH—C(═O)—O—CH2—CH3, —NH—C(═O)—O—C—(CH3)3, —NH—C(═O)—NH—CH3, —NH—C(═N—C(═O)—O—C—(CH3)3)—NH—C(═O)—O—C—(CH3)3, —N(C(═O)—O—C—(CH3)3)—C(═NH)—NH—C(═O)—O—C—(CH3)3,
• x is 1 or 2;
• Y is CH2 or C═O;
• W is CH2, NH or NR′″;
• Z is H or CH3;
• J is —H, —(CH2)m—OH, —C(═O)—CH2)m—OH, —C(═O)—CH2)m—N(v1)(v2), —C(═O)—O—(CH2)m—CH3, —O—(CH2)m—CH3, —O—(CH2)m—N(v1)(v2), —O—(CH2)m—OH, —C(═O)—NH—(CH2)m—CH3, —C(═O)—NH—(CH2)m—N(v1)(v2), —C(═O)—NH—(CH2)m—S(v1), —C(═O)—NH—CH(—C(═O)—N(v1)(v2))2, —C(═O)—NH—CH(—C(═O)—OH)—(CH2)m—N(v1)(v2), —C(═O)—NH—(CH2)m—NH—C(═O)—CH(N(v1)(v2))((CH2)m—N(v1)(v2), —C(═O)—NH—CH(—C(═O)—N(v1)(v2)—(CH2)m—N(v1)(v2), an omega amino aliphatic, terminal aryl or aralkyl group, any single natural or unnatural α-amino acid, β-amine acid or α, α-disubstituted amino acid in combination with one of the foregoing groups defining J, or any single natural or unnatural α-amino acid, β-amino acid or α, α-disubstituted amino acid, including all (R) and (S) configurations of any of the foregoing;
• R′″ is an acyl, a C1 to C17 linear or branched alkyl chain, a C2 to C19 linear or branched alkyl acyl chain, a C1 to C17 linear or branched omega amino aliphatic, or a C1 to C17 linear or branched omega amino aliphatic acyl;
• v1 and v2 are each independently H or a C1 to C17 linear or branched alkyl chain;
• n is 0, 1 or 2;
• m is 0 to 17;
• y is 1 to 5;
• and the carbon atoms marked with an asterisk can have any stereochemical configuration;
• with the proviso that at least one of Aaa1, Aaa3 through Aaa12, Aaa14 or Aaa15 is an amino acid surrogate.